Copenhagen Muscle Research Centre, Department of Human Physiology, Institute of Exercise and Sport Sciences, University of Copenhagen, Copenhagen, Denmark
Lipids as fuel for energy provision ...originate from different sources: albumin-bound long-chain fatty acids (LCFA) in the blood plasma, circulating very-low-density lipoproteins-triacylglycerols (VLDL-TG), fatty acids from triacylglycerol located in the muscle cell (IMTG), and possibly fatty acids liberated from adipose tissue adhering to the muscle cells. The regulation of utilization of the different lipid sources in skeletal muscle during exercise is reviewed, and the influence of diet, training, and gender is discussed. Major points deliberated are the methods utilized to measure uptake and oxidation of LCFA during exercise in humans. The role of the various lipid-binding proteins in transmembrane and cytosolic transport of lipids is considered as well as regulation of lipid entry into the mitochondria, focusing on the putative role of AMP-activated protein kinase (AMPK), acetyl CoA carboxylase (ACC), and carnitine during exercise. The possible contribution to fuel provision during exercise of circulating VLDL-TG as well as the role of IMTG is discussed from a methodological point of view. The contribution of IMTG for energy provision may not be large, covering 10% of total energy provision during fasting exercise in male subjects, whereas in females, IMTG may cover a larger proportion of energy delivery. Molecular mechanisms involved in breakdown of IMTG during exercise are also considered focusing on hormone-sensitive lipase (HSL). Finally, the role of lipids in development of insulin resistance in skeletal muscle, including possible molecular mechanisms involved, is discussed.
Address for reprint requests and other correspondence: Address for reprint requests and other correspondence: B. Kiens, Copenhagen Muscle Research Centre, Dept. of Human Physiology, Institute of Exercise and Sports Sciences, Univ. of Copenhagen, 13 Universitetsparken, DK-2100 Copenhagen, Denmark (e-mail: bkiens{at}aki.ku.dk )
Fatty acids (FAs) as fuel for energy utilization during exercise originate from different sources: FAs transported in the circulation either bound to albumin or as triacylglycerol (TG) carried by ...very low density lipoproteins and FAs from lipolysis of muscle TG stores. Despite a high rate of energy expenditure during high intensity exercise the total FA oxidation is suppressed to below that observed during moderate intensity exercise. Although this has been known for many years, the mechanisms behind this phenomenon are still not fully elucidated. A failure of adipose tissue to deliver sufficient FAs to exercising muscle has been proposed, but evidence is emerging that factors within the muscle might be of more importance. The high rate of glycolysis during high intensity exercise might be the ‘driving force’ via the increased production of acetyl‐CoA, which in turn is trapped by carnitine. This will lead to decreased availability of free carnitine for long chain FA transport into mitochondria. This review summarizes our present view on how FA metabolism is regulated during exercise with a special focus on the limitations in FA oxidation in the transition from moderate to high intensity exercise in humans.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Growing evidence supports that pharmacological application of growth differentiation factor 15 (GDF15) suppresses appetite but also promotes sickness-like behaviors in rodents via GDNF family ...receptor α-like (GFRAL)-dependent mechanisms. Conversely, the endogenous regulation of GDF15 and its physiological effects on energy homeostasis and behavior remain elusive. Here we show, in four independent human studies that prolonged endurance exercise increases circulating GDF15 to levels otherwise only observed in pathophysiological conditions. This exercise-induced increase can be recapitulated in mice and is accompanied by increased Gdf15 expression in the liver, skeletal muscle, and heart muscle. However, whereas pharmacological GDF15 inhibits appetite and suppresses voluntary running activity via GFRAL, the physiological induction of GDF15 by exercise does not. In summary, exercise-induced circulating GDF15 correlates with the duration of endurance exercise. Yet, higher GDF15 levels after exercise are not sufficient to evoke canonical pharmacological GDF15 effects on appetite or responsible for diminishing exercise motivation.
This review summarizes how fatty acid (FA) oxidation is regulated in skeletal muscle during exercise. From the available evidence it seems that acetyl-CoA availability in the mitochondrial matrix ...adjusts FA oxidation to exercise intensity and duration. This is executed at the step of mitochondrial fatty acyl import, as the extent of acetyl group sequestration by carnitine determines the availability of carnitine for the carnitine palmitoyltransferase 1 (CPT1) reaction. The rate of glycolysis seems therefore to be central to the amount of β-oxidation-derived acetyl-CoA that is oxidized in the tricarboxylic acid (TCA) cycle. FA oxidation during exercise is also determined by FA availability to mitochondria, dependent on trans-sarcolemmal FA uptake via cluster of differentiation 36/SR-B2 (CD36) and FAs mobilized from myocellular lipid droplets.
The regulation of fatty acid (FA) oxidation during exercise is subject to multisite control allowing flexible regulation of metabolism.
FA uptake is facilitated via cluster of differentiation 36/SR-B2 (CD36), which translocates to the sarcolemma at the onset of muscle contractions, thereby increasing intracellular FA availability.
Carnitine availability plays an essential role in the regulation of FA oxidation. Sequestering of acetyl-CoA to carnitine by carnitine acetyltransferase (CAT) alters the free carnitine content in muscle thereby influencing the carnitine palmitoyltransferase 1 (CPT1) reaction and in turn mitochondrial FA import and oxidation. This scenario may explain the lower FA oxidation at higher exercise intensities where a high glycolytic rate leads to acetyl-CoA excess, whereas the potential for FA import into the tricarboxylic acid cycle is enhanced when the glycolytic rate is low, as during prolonged low-intensity exercise.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Protein phosphorylation dynamically integrates environmental and cellular information to control biological processes. Identifying functional phosphorylation amongst the thousands of phosphosites ...regulated by a perturbation at a global scale is a major challenge. Here we introduce 'personalized phosphoproteomics', a combination of experimental and computational analyses to link signaling with biological function by utilizing human phenotypic variance. We measure individual subject phosphoproteome responses to interventions with corresponding phenotypes measured in parallel. Applying this approach to investigate how exercise potentiates insulin signaling in human skeletal muscle, we identify both known and previously unidentified phosphosites on proteins involved in glucose metabolism. This includes a cooperative relationship between mTOR and AMPK whereby the former directly phosphorylates the latter on S377, for which we find a role in metabolic regulation. These results establish personalized phosphoproteomics as a general approach for investigating the signal transduction underlying complex biology.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Regular physical activity has a positive impact on cognition and brain function. Here we investigated if a single bout of exercise can improve motor memory and motor skill learning. We also explored ...if the timing of the exercise bout in relation to the timing of practice has any impact on the acquisition and retention of a motor skill. Forty-eight young subjects were randomly allocated into three groups, which practiced a visuomotor accuracy-tracking task either before or after a bout of intense cycling or after rest. Motor skill acquisition was assessed during practice and retention was measured 1 hour, 24 hours and 7 days after practice. Differences among groups in the rate of motor skill acquisition were not significant. In contrast, both exercise groups showed a significantly better retention of the motor skill 24 hours and 7 days after practice. Furthermore, compared to the subjects that exercised before practice, the subjects that exercised after practice showed a better retention of the motor skill 7 days after practice. These findings indicate that one bout of intense exercise performed immediately before or after practicing a motor task is sufficient to improve the long-term retention of a motor skill. The positive effects of acute exercise on motor memory are maximized when exercise is performed immediately after practice, during the early stages of memory consolidation. Thus, the timing of exercise in relation to practice is possibly an important factor regulating the effects of acute exercise on long-term motor memory.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Hyperinsulinemia is the hallmark of insulin resistance in obesity, and the relative importance of insulin clearance, insulin resistance, and insulin hypersecretion has been widely debated. On the ...basis of recent experimental evidence, we summarize existing evidence to suggest hepatic insulin clearance as a major and immediate regulator of systemic insulin concentrations responding within days to altered dietary energy and, in particular, carbohydrate intake. Hepatic insulin clearance seems to be closely associated with opposite alterations in hepatic lipid content and glucose production, providing a potential mechanistic link to hepatic insulin sensitivity. The molecular regulation of insulin clearance in the liver is likely to involve changes in insulin binding and receptor internalization in response to the dietary alterations, the molecular mechanisms of which await further research.
Dietary protein dilution (DPD) promotes metabolic-remodelling and -health but the precise nutritional components driving this response remain elusive. Here, by mimicking amino acid (AA) supply from a ...casein-based diet, we demonstrate that restriction of dietary essential AA (EAA), but not non-EAA, drives the systemic metabolic response to total AA deprivation; independent from dietary carbohydrate supply. Furthermore, systemic deprivation of threonine and tryptophan, independent of total AA supply, are both adequate and necessary to confer the systemic metabolic response to both diet, and genetic AA-transport loss, driven AA restriction. Dietary threonine restriction (DTR) retards the development of obesity-associated metabolic dysfunction. Liver-derived fibroblast growth factor 21 is required for the metabolic remodelling with DTR. Strikingly, hepatocyte-selective establishment of threonine biosynthetic capacity reverses the systemic metabolic response to DTR. Taken together, our studies of mice demonstrate that the restriction of EAA are sufficient and necessary to confer the systemic metabolic effects of DPD.
In response to skeletal muscle contraction during exercise, paracrine factors coordinate tissue remodeling, which underlies this healthy adaptation. Here we describe a pH-sensing metabolite signal ...that initiates muscle remodeling upon exercise. In mice and humans, exercising skeletal muscle releases the mitochondrial metabolite succinate into the local interstitium and circulation. Selective secretion of succinate is facilitated by its transient protonation, which occurs upon muscle cell acidification. In the protonated monocarboxylic form, succinate is rendered a transport substrate for monocarboxylate transporter 1, which facilitates pH-gated release. Upon secretion, succinate signals via its cognate receptor SUCNR1 in non-myofibrillar cells in muscle tissue to control muscle-remodeling transcriptional programs. This succinate-SUCNR1 signaling is required for paracrine regulation of muscle innervation, muscle matrix remodeling, and muscle strength in response to exercise training. In sum, we define a bioenergetic sensor in muscle that utilizes intracellular pH and succinate to coordinate tissue adaptation to exercise.
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•Mouse and human muscle selectively release succinate during exercise•Muscle cells release succinate by pH-gated secretion via MCT1•Extracellular succinate regulates paracrine responses to exercise through SUCNR1•SUCNR1 signaling mediates muscle remodeling responses to exercise training
Reddy et al. identify a bioenergetic sensor that uses pH and succinate to regulate muscle tissue adaptation to exercise.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Exercise is essential in regulating energy metabolism and whole-body insulin sensitivity. To explore the exercise signaling network, we undertook a global analysis of protein phosphorylation in human ...skeletal muscle biopsies from untrained healthy males before and after a single high-intensity exercise bout, revealing 1,004 unique exercise-regulated phosphosites on 562 proteins. These included substrates of known exercise-regulated kinases (AMPK, PKA, CaMK, MAPK, mTOR), yet the majority of kinases and substrate phosphosites have not previously been implicated in exercise signaling. Given the importance of AMPK in exercise-regulated metabolism, we performed a targeted in vitro AMPK screen and employed machine learning to predict exercise-regulated AMPK substrates. We validated eight predicted AMPK substrates, including AKAP1, using targeted phosphoproteomics. Functional characterization revealed an undescribed role for AMPK-dependent phosphorylation of AKAP1 in mitochondrial respiration. These data expose the unexplored complexity of acute exercise signaling and provide insights into the role of AMPK in mitochondrial biochemistry.
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•Identification of the human muscle acute exercise signaling repertoire•Integrated AMPK substrate prediction in human muscle and cells•Targeted validation of exercise-regulated AMPK substrates•AKAP1 phosphorylation by AMPK that regulates mitochondrial respiration
Combining phosphoproteomics, biochemical, and bioinformatics approaches, Hoffman et al. perform a global analysis of exercise signaling in human skeletal muscle and reveal an interconnected network of kinases and AMPK substrates in response to exercise. Among these, AKAP1 is shown to regulate mitochondrial respiration via AMPK-dependent phosphorylation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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